CN106535933A - 包含核受体配体的免疫诱导促进用组合物以及疫苗药物组合物 - Google Patents
包含核受体配体的免疫诱导促进用组合物以及疫苗药物组合物 Download PDFInfo
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Abstract
本发明目的在于提供用于对各种抗原进行免疫诱导的能够普遍使用的、发挥出高的诱导效果的免疫诱导促进用组合物和疫苗药物组合物。本发明是包含一种以上核受体配体的免疫诱导促进用组合物;本发明是用于免疫诱导的、包含抗原和作为一种以上核受体配体的免疫诱导促进组合物的疫苗药物组合物。
Description
技术领域
本发明涉及包含核受体配体的免疫诱导促进用组合物、以及包含免疫诱导促进用组合物的、用于免疫诱导的疫苗药物组合物。
背景技术
通常广泛使用的疫苗是对通过微生物或病毒等病原体或其一部分的毒性进行弱化、无效化的物质,通过对生物体给药来诱导用于预防感染病的免疫。
吞噬病毒、微生物等外来性异物的树突状细胞转移到淋巴结,对幼稚T细胞(Th0细胞)传递异物的信息,诱导辅助(helper)T细胞的分化。Th0细胞收到树突状细胞的各种信息,分化成负责细胞性免疫的1型辅助T细胞(Th1细胞)、负责体液免疫的2型辅助T细胞(Th2细胞)(参照例如,[非专利文献1]和[非专利文献2])。
Toll样受体(TLR)始于树突状细胞,多表达于负责自然免疫系的免疫活性细胞表面上,通过接收TLR配体而活性化,促进辅助T细胞的分化。由此,免疫反应被活化(参照例如[非专利文献3])。一直以来,免疫活化中,只知道通过TLR刺激的反应路径,除此以外的反应路径还不明确。
另一方面,已知霍乱毒素、大肠杆菌非耐热性毒素等毒素类;通过抗原的缓释性来提高免疫反应效果那样的油脂系佐剂中,也具有免疫活化作用,但关于其安全性与效果的平衡存在问题(例如,参照[非专利文献4])。
现有技术文献
非专利文献
非专利文献1:Lipscomb MF.et al.,Physiol Rev.,82,97-130(2002)
非专利文献2:Zhou L.et al.,Immunity,30,646-655(2009)
非专利文献3:Mazzoni A.et al.,J Leukoc Biol.,75,721-730(2004)
非专利文献4:Stevceva L.et al.,Curr Pharm Des,11,801-811(2005)
发明内容
发明要解决的问题
本发明鉴于上述现状,目的在于提供用于对各种抗原进行免疫诱导的、能够普遍使用的、有效地发挥细胞性免疫、体液免疫这样的生物体防御作用的免疫诱导促进用组合物和疫苗药物组合物。
用于解决问题的方案
本发明人等发现,树突状细胞吞噬抗原时,通过药物由外部施加刺激,如TLR配体那样,自然免疫系被活性化,从而能够诱导有效的免疫反应。并且,通过控制作为免疫反应起点的树突状细胞,能够有效地诱导抗原特异的免疫反应,着眼于这一点进行了深入的研究。结果,令人惊奇的发现是,通过使用对与局部存在于细胞表面的TLR完全不同的、在细胞内特别是核内存在的、承担着对核内的信息传导和转录控制的核受体起作用的药物,能够进行抗原特异的免疫诱导。
即,本发明发现,通过将核受体配体与抗原一起或分别地、对相同部位或不同的部位、直接对生物体进行给药,利用不介由由TLR配体带来的TLR刺激的反应,从而能够有效地诱导抗原特异的免疫反应。
即,本发明为特征在于包含核受体配体的免疫诱导促进用组合物。
本发明的免疫诱导促进用组合物中的上述核受体配体优选为选自由类视黄醇受体激动剂、类视黄醇X受体激动剂、甲状腺激素受体激动剂和雌激素受体调节剂组成的组中的至少一种。
本发明的免疫诱导促进用组合物中的上述核受体配体优选为选自由类视黄醇受体激动剂、甲状腺激素受体激动剂和雌激素受体调节剂组成的组中的至少一种,用于体液免疫诱导。
本发明的免疫诱导促进用组合物中的上述核受体配体优选为类视黄醇受体激动剂和/或类视黄醇X受体激动剂,用于细胞性免疫诱导。
本发明的免疫诱导促进用组合物进而优选包含辅助肽。
另外,本发明为特征在于包含用于免疫诱导的抗原和上述免疫诱导促进用组合物的疫苗药物组合物。
本发明的疫苗药物组合物优选对体表面上给药。
本发明的疫苗药物组合物优选通过皮内注射、皮下注射或肌肉注射给药。
另外,本发明的一个方式中,包含上述核受体配体和以TLR配体为代表的免疫诱导促进剂的免疫诱导促进用组合物和疫苗药物组合物发挥出更高的体液免疫诱导效果。
以下,对于本发明进行详细说明。
本发明的免疫诱导促进用组合物和疫苗药物组合物用于抗原特异的免疫诱导。
抗原特异的免疫诱导中,可列举出:诱导细胞毒性T细胞等的细胞性免疫以及促进抗体产生的体液免疫。
对细胞性免疫诱导效果定量测定的方法,没有特别的限定,开发出了各种各样的方法,例如,可以通过使用了免疫评价用模型动物的免疫诱导实验和ELISPOT方法(IFN-γ)进行测定。作为用于ELISPOT方法的样品,可列举出例如,免疫评价用模型动物的脾脏。
对于体液免疫诱导效果进行定量测定的方法,没有特别的限定,开发出了各种方法,例如,可以通过使用了免疫评价用模型动物的免疫诱导实验和ELISA法(抗原特异性IgG抗体)进行测定。作为用于ELISA法的样品,可列举出例如,免疫评价用模型动物的血液。
本发明的免疫诱导促进用组合物包含作为核受体配体的免疫诱导促进剂。另外,本发明的疫苗药物组合物包含抗原和上述免疫诱导促进用组合物。
通过包含上述抗原和作为上述核受体配体的免疫诱导促进剂,本发明的疫苗药物组合物能够有效地诱导抗原特异的免疫反应。
本说明书中使用时,术语“抗原”是指能够诱导免疫应答的所有的物质。对于上述抗原,没有特别的限定,可列举出例如:蛋白质、肽等。要求抗原的皮肤渗透性的经皮给药中,优选使用分子量小的抗原,可以使用例如由约8~12个氨基酸形成的肽。
对于上述抗原,没有特别的限定,可列举出例如:癌抗原肽、来自感染性病原体的抗原、感染性抗原肽。
本说明书中使用时,术语“癌”是指癌基因的异常表达。作为上述癌,可列举出例如:造血器官肿瘤、实体癌等伴随有过剩表达的癌。
本说明书中使用时,术语“基因的异常的表达”是指某细胞中的该基因的表达水平与相同组织的其他细胞相比较,以例如2倍以上、4倍以上等倍率显著地上升或降低。
本说明书中使用时,术语“过剩表达”是指异常的表达为表达水平的上升。基因的表达水平可以使用该技术领域公知的任意方法容易地测定。
作为上述癌基因,可列举出例如:存活蛋白基因、GPC3基因、HER2/neu基因、MAGE3基因、MAGE A1基因、MAGE A3/A6基因、MAGE A4基因、MAGE12基因、蛋白酶-3基因、AFP基因、CA-125基因、CD44基因、CEA基因、c-Kit基因、c-met基因、c-myc基因、L-myc基因、COX2基因、Cyclin(细胞周期蛋白)D1基因、Cytokeratin(细胞角蛋白)-7基因、Cytokeratin-19基因、Cytokeratin-20基因、E2F1基因、E2F3基因、EGFR基因、Gli1基因、hCGβ基因、HIF-1α基因、HnRNP A2/B1基因、hTERT基因、MDM基因、MDR-1基因、MMP-2基因、MMP-9基因、Muc-1基因、Muc-4基因、Muc-7基因、NSE基因、ProGRP基因、PSA基因、RCAS1基因、SCC基因、Thymoglobulin(抗胸腺细胞球蛋白)基因、VEGF-A基因、VEGF-A基因等。
伴随着上述存活蛋白基因异常表达的癌中,包括恶性淋巴瘤、膀胱癌、肺癌、大肠癌等,但不限定于此。伴随上述GPC3基因异常表达的癌中包括肝癌、胆管癌、胃癌等,但不限定于此。伴随着上述HER2/neu基因异常表达的癌中包括乳癌、胃癌、卵巢癌、子宫癌、膀胱癌、非小细胞肺癌、前列腺癌等,但不限定于此。伴随着上述MAGE3基因异常表达的癌中,包括黑色素瘤、肺癌、头颈部癌、膀胱癌、胃癌、食道癌、肝脏癌等,但不限定于此。伴随着上述蛋白酶-3基因异常表达的癌包括急性骨髄性白血病、胰脏癌等,但不限定于此。
本说明书中使用时,术语“癌抗原”是指在肿瘤细胞或癌细胞中特异性表达、能够诱导细胞性免疫应答的蛋白质、肽等物质。
本说明书中使用时,术语“癌抗原肽”是来自于癌抗原蛋白质的部分肽、并且能够诱导细胞性免疫应答的物质。通常,癌抗原肽通过作为癌基因产物的癌抗原蛋白质在癌细胞内被分解而产生,通过MHC I类分子在癌细胞的表面呈递。
上述癌抗原肽可以是由癌细胞分离和纯化的内源性的癌抗原肽,也可以是具有与内源性的癌抗原肽相同氨基酸序列的合成肽。作为上述癌抗原肽,具体而言,优选为存活蛋白2B肽、GPC3肽、HER2/neu_A24肽、MAGE3_A24肽、PR1肽、HER2/neu_A02肽、MAGE3_A02肽、HER2/neu_E75肽、MUC1肽或者它们的变异肽。
本说明书中使用时,术语“存活蛋白2B肽”是指由序列Ala Tyr Ala Cys Asn ThrSer Thr Leu(序列号1)组成的、来自于癌基因产物存活蛋白的肽。
本说明书中使用时,术语“GPC3肽”是指由序列Glu Tyr Ile Leu Ser Leu GluGlu Leu(序列号2)组成的、来自于癌基因产物GPC3的肽。
本说明书中使用时,术语“HER2/neu_A24肽”是指由序列Thr Tyr Leu Pro ThrAsn Ala Ser Leu(序列号3)组成的、来自癌基因产物HER2/neu的HLA-A24限制性肽。
本说明书中使用时,术语“MAGE3_A24肽”是指由序列Ile Met Pro Lys Ala GlyLeu Leu Ile(序列号4)组成的、来自癌基因产物MAGE3的HLA-A24限制性肽。
本说明书中使用时,术语“PR1肽”是指由序列Val Leu Gln Glu Leu Asn Val ThrVal(序列号5)组成的、来自癌基因产物蛋白酶-3的肽。
本说明书中使用时,术语“HER2/neu_A02肽”是指由序列Lys Val Phe Gly SerLeu Ala Phe Val(序列号6)组成的、来自癌基因产物HER2/neu的HLA-A02限制性肽。
本说明书中使用时,术语“MAGE3_A02肽”是指由序列Lys Val Ala Glu Ile ValHis Phe Leu(序列号7)组成的、来自癌基因产物MAGE3的HLA-A02限制性肽。
本说明书中使用时,术语“HER2/neu_E75肽”是指由序列Lys Ile Phe Gly SerLeu Ala Phe Leu(序列号8)组成的、来自癌基因HER2/neu产物(HER2蛋白质)的肽。
本说明书中使用时,术语“MUC1肽”是指由序列Ser Thr Ala Pro Pro Val HisAsn Val(序列号9)组成的、来自作为在很多癌细胞上高表达的糖蛋白的MUC1蛋白的肽。
本说明书中使用时,术语“变异肽”是指肽的全部或一部分氨基酸被置换或修饰等而变异的肽。
对于上述变异肽,没有特别的限定,可列举出例如:(a)肽的氨基酸序列中1个~多个(例如,1个、2个、3个、4个或5个)氨基酸进行了置换、缺失或添加而成的氨基酸序列所组成的肽;(b)肽的氨基酸序列中全部或一部分氨基酸(例如,1个、2个、3个、4个、5个、6个、7个、8个、9个或10个)被修饰的氨基酸序列所组成的肽等。
对于上述变异肽所具有的氨基酸的修饰,没有特别的限定,可列举出例如:乙酰化、甲基化等烷基化、糖基化、羟基化、羧基化、醛化、磷酸化、磺酰化、甲酰化、肉豆蔻酰化、棕榈酰化、硬脂酰化等脂肪链附加修饰;辛酰基化、酯化、酰胺化、脱酰胺化、胱氨酸修饰、谷胱甘肽修饰、巯基乙酸修饰等二硫化物键形成修饰;糖化、泛素化、琥珀酰亚胺形成、谷胺酰化、异戊二烯化等。
上述变异肽也可以为包含1个以上氨基酸的置换、缺失或添加与1个以上氨基酸的修饰组合的肽。
上述来自感染性病原体的抗原是指能够成为由被检生物体产生的免疫应答靶标的所有的物质。另外,上述来自感染性病原体的抗原也可以为与免疫活性细胞接触时,成为免疫应答(例如,免疫活性细胞的成熟、细胞因子产生量的増加、抗体产生的促进等)靶标的物质。
作为本发明的体液免疫诱导用的疫苗药物组合物,可以通过将上述来自感染性病原体的抗原和体液免疫诱导用的上述免疫诱导促进用组合物一起对对象给药来处置(例如,治疗或预防)感染性疾病。
作为本发明的细胞性免疫诱导用的疫苗药物组合物通过将上述癌抗原和细胞性免疫诱导用的上述免疫诱导促进用组合物一起对对象给药,从而对癌进行处置(例如,治疗或预防)。
作为来自上述感染性病原体的抗原,只要为感染性病原体和来自感染性病原体的抗原,则没有特别的限定。
作为因上述感染性病原体患上的疾病,没有特别限定,例如可列举出由腺病毒(例如,人腺病毒)、疱疹病毒(例如,单纯疱疹病毒、水痘/带状疱疹病毒、巨细胞病毒、人疱疹病毒、卡波西肉瘤相关疱疹病毒)、小核糖核酸病毒(例如,脊髓灰质炎病毒、感冒病毒、甲型肝炎病毒)、痘病毒(例如,天花病毒、痘苗病毒、传染性软疣病毒)、小核糖核酸病毒(例如,鼻病毒、肠道病毒)、正粘病毒(例如,流感病毒)、副粘病毒(例如,副流感病毒、腮腺炎病毒、麻疹病毒、呼吸道合胞体病毒(RSV)、新城疫病毒)、细小病毒(例如,腺随伴病毒)、外衣病毒(例如,风疹病毒)、冠状病毒(例如,SARS冠状病毒)、嗜肝DNA病毒(例如,乙型肝炎病毒)、黄病毒(例如,乙型脑炎病毒、黄热病病毒、登革热病毒、西尼罗热病毒、圣路易脑炎病毒、墨累山谷脑炎病毒、丙型肝炎病毒、庚型肝炎病毒)、肝炎病毒(例如,戊型肝炎病毒)、乳头瘤病毒(例如,人乳头瘤病毒)、杯状病毒(例如,诺如病毒)、弹状病毒(例如,狂犬病毒、水泡性口炎病毒)、纤丝病毒(例如,埃博拉出血热病毒)、沙粒病毒(例如,拉沙病毒、丁型肝炎病毒)、布尼亚病毒(例如,加里福尼亚脑炎病毒、裂谷热病毒)、呼肠孤病毒(例如,轮状病毒)、逆转录病毒(例如,人类免疫缺陷病毒(HIV)、成人T细胞白血病病毒)等的病毒感染患上的疾病等病毒疾病;由埃希氏菌属、肠杆菌、沙门氏菌、葡萄球菌、志贺菌、李斯特菌、气杆菌、螺杆菌、克雷伯菌、变形杆菌、假单胞菌、链球菌、衣原体、支原体、肺炎球菌、奈瑟菌、梭菌、芽孢杆菌、棒状杆菌、分枝杆菌、弯曲杆菌、弧菌、沙雷氏菌、普罗威登斯菌、色杆菌、布鲁氏菌、耶尔森菌、嗜血杆菌、博德特杆菌等的细菌感染患上的疾病等细菌疾病;衣原体、念珠菌病、曲霉菌病、组织胞浆菌病、隐球菌性髓膜炎等真菌疾病;疟疾、肺孢子虫肺炎、利什曼病、隐孢子虫病、弓形虫病、锥虫感染等。
本说明书中使用时,术语“感染性抗原肽”是指源自来自感染性病原体的抗原蛋白质并且能够诱导细胞性免疫应答的部分肽。通常,作为上述来自感染性病原体的抗原,优选为IPEP87肽、HBVenv肽或者它们的变异肽。
本说明书中使用时,术语“IPEP87肽”是指由序列Asp Leu Met Gly Tyr Ile ProAla Val(序列号10)组成的、来自丙型肝炎病毒(HCV)蛋白质的肽。
本说明书中使用时,术语“HBVenv肽”是指由序列Trp Leu Ser Leu Leu Val ProPhe Val(序列号11)组成的、来自乙型肝炎病毒(HBV)蛋白质的肽。
上述的肽可以是游离形或者药理学允许的任意盐形的形式。
作为上述药理学允许的任意的盐,可列举出例如:酸盐(例如,乙酸盐、TFA盐、盐酸盐、硫酸盐、磷酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、草酸盐、氢溴酸盐、琥珀酸盐、硝酸盐、苹果酸盐、柠檬酸盐、油酸盐、棕榈酸盐、丙酸盐、蚁酸盐、苯甲酸盐、苦味酸盐、苯磺酸盐、十二烷基硫酸盐、甲磺酸盐、对甲苯磺酸盐、戊二酸盐、各种氨基酸盐)、金属盐(例如,碱金属盐(例如,钠盐、钾盐)、碱土金属盐(例如,钙盐、镁盐)、铝盐)、胺盐(例如,三乙基胺盐、苄基胺盐、二乙醇胺盐、叔丁基胺盐、二环己胺盐、精氨酸盐、二甲基铵盐、铵盐等)等。其中,优选为乙酸盐或TFA盐。
上述的肽可以使用以公知的方法合成或产生、分离和纯化而成的物质。
一个优选的方式中,通过将含有核受体配体的免疫诱导促进用组合物与抗原一起或者分别给药;或者,通过将含有抗原和免疫诱导促进用组合物的疫苗药物组合物给药来实现免疫的效果的诱导。
本说明书中使用时,术语“免疫诱导促进剂”是指将一起给药的诱导抗原免疫的效率与不这样做的效率相比较、能够改善的所有的物质;对于促进免疫诱导的作用机理没有限定,是指本说明书中特定的物质。
一个优选的方式中,通过给予含有核受体配体和抗原的疫苗药物组合物来实现,所述核受体配体是选自由类视黄醇受体激动剂、类视黄醇X受体激动剂、甲状腺激素受体激动剂和雌激素受体调节剂组成的组中的一种以上。
本说明书中使用时,术语“核受体配体”是指对核受体或者与其关联的蛋白质起作用的物质。一个方式中,核受体配体是免疫诱导促进剂的一种。
作为核受体配体,可以使用类视黄醇受体配体。进而,类视黄醇受体配体优选为类视黄醇受体激动剂。本说明书中使用时,术语“类视黄醇受体激动剂”是指该物质自身具有作用于类视黄醇受体的功能的物质。作为类视黄醇受体激动剂,可列举出:维生素A、视黄醇棕榈酸酯、视黄醇乙酸酯、视黄醇丙酸酯、他扎罗汀、依曲替酯、维生素A酸、维甲酸、异维甲酸、阿利维甲酸、芬维A胺、他米巴罗汀、帕罗伐汀及它们的衍生物、以及它们的药理学允许的盐等。
作为核受体配体,可以使用类视黄醇X受体配体。进而,类视黄醇X受体配体优选为类视黄醇X受体激动剂。
本说明书中使用时,术语“类视黄醇X受体激动剂”是指该物质自身具有作用于类视黄醇X受体的功能的物质。作为类视黄醇X受体激动剂,可列举出:蓓萨罗丁及它们的衍生物、以及它们的药理学允许的盐等。
作为核受体配体,可以使用甲状腺激素受体配体。进而,甲状腺激素受体配体优选为甲状腺激素受体激动剂。
本说明书中使用时,术语“甲状腺激素受体激动剂”是指该物质自身具有作用于甲状腺激素受体的功能的物质。作为甲状腺激素受体激动剂,可列举出:替拉曲可、左旋甲状腺素、碘塞罗宁、甲状腺、Liotrix、Sobetirome及它们的衍生物、以及它们的药理学允许的盐等。
作为核受体配体,可以使用雌激素受体配体。进而,雌激素受体配体优选为雌激素受体调节剂。
本说明书中使用时,术语“雌激素受体调节剂”是指该物质自身具有作用于雌激素受体、具有弱的受体激动和阻碍雌激素结合的功能的物质。作为雌激素受体调节剂,可列举出:氯米芬、雷洛昔芬、他莫昔芬、托瑞米芬及它们的衍生物、以及它们的药理学允许的盐等。
本说明书中所谓的“盐”可以为任意的有机酸或无机酸,但优选为药理学允许的盐。
本说明书中所谓的“药理学允许的盐”是指不会对给药对象带来有害作用且不会使疫苗药物组合物中的配混成分的药理活性消失的盐,可列举出:例如:无机酸盐(例如,盐酸盐、磷酸盐)、有机酸盐(例如,乙酸盐、苯二甲酸盐、TFA盐、柠檬酸盐)、金属盐(例如,碱金属盐(例如,钠盐、钾盐)、碱土金属盐(例如,钙盐、镁盐)、铝盐)、胺盐(例如,三乙基胺盐、苄基胺盐、二乙醇胺盐、叔丁基胺盐、二环己基胺盐、精氨酸盐、二甲基铵盐、铵盐)等。
本发明的免疫诱导促进用组合物中的作为上述核受体配体的免疫诱导促进剂的含量,没有特别的限定,基于组合物的总重量,优选包含0.0001~100重量%,更优选包含0.001~80重量%,更优选包含0.01~50重量%。最优选包含0.05~20重量%。
对于本发明的疫苗药物组合物中的上述抗原含量,没有特别限定,基于组合物的总重量优选为0.000001~50重量%,更优选为0.00001~20重量%。
本发明的疫苗药物组合物中的作为上述核受体配体的免疫诱导促进剂的含量,没有特别限定,相对于1重量份抗原,优选为0.001~10000重量份,更优选为0.01~10000重量份。
上述免疫诱导促进剂的含量小于下限值0.001重量份时,不能充分地得到免疫诱导效果。上述免疫诱导促进剂的含量大于上限值10000重量份时,安全性会成为问题。
本发明的疫苗药物组合物除了上述核受体配体的免疫诱导促进剂之外,在不有损本发明效果的范围内,也可以进一步含有第二免疫诱导促进剂。对于上述第二免疫诱导促进剂,没有特别的限定,可列举出例如辅助肽等。
通过组合使用上述第二免疫诱导促进剂,能够进一步有效地促进免疫诱导。
另外,作为第二免疫诱导促进剂使用辅助肽的情况下,更优选作为细胞性免疫诱导用的免疫部活化剂而使用。
本说明书中使用时,术语“辅助肽”是指对辅助T细胞进行活性化的所有的肽。
作为上述辅助肽的第二细胞性免疫诱导促进剂,可列举出例如:来自结核菌的辅助肽、来自麻疹病毒的辅助肽、来自乙型肝炎病毒的辅助肽、来自丙型肝炎病毒的辅助肽、来自沙眼的辅助肽、来自热带疟原虫孢子体的辅助肽、来自钥孔戚血蓝蛋白(keyholelimpet haemocyanin)的辅助肽、来自破伤风毒素的辅助肽、来自百日咳毒素的辅助肽、来自白喉毒素的辅助肽、来自癌细胞的辅助肽(例如,IMA-MMP-001辅助肽、CEA-006辅助肽、MMP-001辅助肽、TGFBI-004辅助肽、HER-2/neu(aa776-790)辅助肽、AE36辅助肽、AE37辅助肽、MET-005辅助肽、BIR-002辅助肽)、通用辅助模拟物(例如,PADRE)、它们的变异肽等。其中,优选为Peptide(肽)-25、变异Peptide-25、PADRE。
本说明书中使用时,术语“PADRE”是指由序列D-Ala Lys cyclohexyl(环己基)-Ala Val Ala Ala Trp Thr Leu Lys Ala Ala D-Ala(序列号12)组成的13氨基酸的肽。
本发明的免疫诱导促进用组合物和疫苗药物组合物中的上述第二免疫诱导促进剂的含量没有特别的限定,相对于1重量份的抗原,优选为0.001~500重量份,更优选为0.005~200重量份,进而优选为0.01~100重量份。上述含量小于下限值0.001重量份时,不能充分地得到免疫诱导效果。上述含量大于上限值500重量份时,安全性存在问题。
本发明的免疫诱导促进用组合物和疫苗药物组合物也可以根据需要含有添加剂。上述添加剂根据基材的主要成分、上述抗原和作为上述核受体配体的免疫诱导促进剂的适合性、意图的给药方案等,可列举出例如:等渗剂、防腐杀菌剂、抗氧化剂、溶解剂、溶解助剂、悬浮化剂、填充剂、pH调节剂、稳定化剂、吸收促进剂、释放速度控制剂、着色剂、增塑剂、交联剂、粘合剂等。这些添加剂可以单独使用或者组合使用2种以上。
本发明的免疫诱导促进用组合物和疫苗药物组合物可以对皮内、皮下或肌肉给药;优选对体表面上给药,更优选经皮给药或经粘膜给药。即,本发明的疫苗药物组合物为皮内、皮下或肌肉给药用疫苗药物组合物,优选为经皮给药用或经粘膜给药用疫苗药物组合物。通过经皮给药或经粘膜给药向对象给予本发明的疫苗药物组合物,由此能够有效地诱导抗原特异的体液免疫。
本说明书中所谓的“对象”是指能够在实用阶段给予疫苗药物组合物来诱导免疫应答的任何动物。上述对象典型地为包括人的哺乳类(例如,小鼠、大鼠、犬、猫、兔子、马、牛、绵羊、猪、山羊、猴、大猩猩)。特别优选的对象是人。
<经粘膜给药用疫苗药物组合物>
作为上述经粘膜给药,可列举出例如:舌下给药、鼻腔给药、颊侧给药、直肠给药、阴道给药等。
上述经粘膜给药用疫苗药物组合物的剂型为例如,凝胶剂(啫喱剂)、霜剂、软膏剂、硬膏剂等半固体剂;液体制剂;散剂、细粒剂、颗粒剂、薄膜剂、片剂、口腔内崩解片(冷冻干燥型)等固体制剂;气溶胶剂等粘膜用喷剂;吸入剂等。这些组合物的划分、定义、性质、制法等是该技术领域公知的,可以参照例如日本药典第16版。另外,对于这些材料,没有特别的限定,可以使用现有已知的物质。
上述剂型中。优选液体制剂、固体制剂(口腔内崩解片(冷冻干燥型)、薄膜剂等)。
作为上述液体制剂所使用的溶剂,可列举出:适量的水、乙醇、甘油、丙二醇等。通过在这些溶剂中分散或溶解配混成分(即,上述抗原、上述作为核受体配体剂的免疫诱导促进剂、根据需要的上述第二免疫诱导促进剂等),从而能够制备液体制剂。
对于上述凝胶剂(啫喱剂)所使用的基材,没有特别的限定,可列举出例如:羧基乙烯基聚合物、凝胶基质、无脂肪性软膏、聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、海藻酸钠、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、塔拉胶、罗望子胶、车前子胶、琼脂、结冷胶、葡甘露聚糖、刺槐豆胶、瓜尔豆胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚醣、EUDRAGIT、酪蛋白、海藻酸烷基酯、明胶、聚乙二醇等水凝胶基材等。通过将这些基材溶解于溶剂中,并配混上述配混成分,从而能够制备具有流动性的凝胶剂或具有成形性的凝胶剂。作为溶剂,优选为水,也可以使用甘油、丙二醇等。
作为上述霜剂所使用的基材,可列举出亲水性软膏、雪花膏等水/油型基材;亲水性凡士林、精制羊毛脂、阿夸弗尔、优塞林、Neocerin、含水羊毛脂、冷霜、亲水Plastibase(液体石蜡与聚乙烯的复合软膏基质)等油/水型基材。通过将这些基材投入到油脂系溶剂或水中,利用均质器等进行高速搅拌,并配混上述配混成分,从而能够制备霜剂。
作为用于上述薄膜剂的基材,没有特别限定,例如可列举出:聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、海藻酸钠、甲基纤维素、羧基乙烯基聚合物、琼脂、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、刺槐豆胶、瓜尔豆胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚醣、甲基丙烯酸氨基烷基酯共聚物E、甲基丙烯酸氨基烷基酯共聚物RS、甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、丙烯酸甲酯-甲基丙烯酸-甲基丙烯酸甲酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、聚乙烯醇缩醛二乙基氨基乙酸酯、酪蛋白及海藻酸烷基酯等。通过将这些基材溶解于水或乙醇等极性有机溶剂中,配混上述配混成分,进行薄膜涂布后使其干燥,从而能够制备薄膜剂。
对于上述散剂、细粒剂、颗粒剂、片剂等所使用的添加剂,没有特别的限定,可列举出例如:乳糖、玉米淀粉、结晶纤维素等赋形剂、羟丙基纤维素、阿拉伯胶等结合剂等。将这些添加剂添加至适量的水或乙醇等溶剂中,配混上述配混成分进行混合搅拌之后,组合造粒、干燥、压片等工序,从而能够制备上述散剂、细粒剂、颗粒剂、片剂等。只要需要,也可以添加硬脂酸镁等润滑剂、羟丙基纤维素、蔗糖等包衣剂。
对于上述口腔内崩解片(冷冻干燥型)中所使用的基材,没有特别限定,可列举出例如:明胶、普兰糖等多糖类、羟丙基纤维素等水凝胶基材。另外,也可以使用甘露醇、海藻糖、山梨醇、甘氨酸等成形剂。通过将这些基材及成形剂溶解于水中,配混上述配混成分,进行分注后使其冷冻干燥,从而能够制备口腔内崩解片(冷冻干燥型)。
作为上述气溶胶剂,可列举出作为内容物的液体制剂、流动性高的凝胶剂、霜剂、散剂等的微粉末。可以将这些内容物使用喷雾装置在气体中以固体或液体的细颗粒的形式分散,由此能够效率良好地对口腔粘膜、鼻腔粘膜等给药部位给药。
<经粘膜给药用免疫诱导促进用组合物>
本发明的经粘膜给药用免疫诱导促进用组合物在对象的各种核受体配体的粘膜给药中,更有效地发挥出一起或分别给药的各种抗原诱导的免疫。
作为上述经粘膜给药用免疫诱导促进用组合物的给药途径和制剂,可以使用与上述经粘膜给药用疫苗药物组合物同样的给药途径和制剂。进而,对于上述经粘膜给药用免疫诱导促进用组合物的制剂制备,可以使用与上述经粘膜给药用疫苗药物组合物的制剂制备所使用的材料相同的材料。
<经皮给药用疫苗药物组合物>
上述经皮给药用疫苗药物组合物的剂型可以为例如:擦剂、露剂(lotion)等外用液体制剂;气溶胶剂等外用喷剂;凝胶剂、胶带剂、巴布剂等贴剂;软膏剂、硬膏剂、霜剂。这些组合物的划分、定义、性质、制法等是该技术领域公知的,可以参照例如日本药典第16版。另外,对于这些材料,没有特别的限定,可以使用现有已知的物质。
上述剂型中,优选为霜剂、贴剂(胶带剂、巴布剂等)。
作为上述擦剂所使用的基材,可列举出水、乙醇、脂肪油、固体石蜡、软石蜡、液体石蜡、甘油、石蜡油、蜜蜡、金属皂、粘液(mucilage)、天然油(例如,杏仁油、玉米油、花生油、蓖麻油、橄榄油或它们的衍生物(例如,聚氧乙烯醚蓖麻油))、羊脂或其衍生物、脂肪酸和/或其酯(例如,硬脂酸、油酸、肉豆蔻酸异丙酯)。
上述露剂是将上述配混成分微细地均匀分散在水性的液体中而得到的制剂,包括悬浮性露剂和乳浊性露剂。作为悬浮剂,可列举出阿拉伯胶、海藻酸钠、羧甲基纤维素钠、甲基纤维素、膨润土等。作为乳化剂,可列举出月桂基硫酸钠、失水山梨醇脂肪酸酯等。
作为上述软膏剂中使用的基材,可列举出:油脂类、蜡、烃化合物等通常作为疏水性基材使用的物质。具体而言,可列举出黄色凡士林、白色凡士林、石蜡、液体石蜡、Plastibase、有机硅等矿物性基材、蜜蜡、动植物性油脂等动植物性基材等。
作为上述霜剂所使用的基材,可列举出亲水性软膏、雪花膏等水/油型基材;亲水性凡士林、精制羊毛脂、阿夸弗尔、优塞林、Neocerin、含水羊毛脂、冷霜、亲水Plastibase等油/水型基材。
作为用于上述凝胶剂的基材,没有特别限定,例如可列举出羧基乙烯基聚合物、凝胶基质、无脂肪性软膏、聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、海藻酸钠、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、塔拉胶、罗望子胶、车前子胶、琼脂、结冷胶、葡甘露聚糖、刺槐豆胶、瓜尔豆胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚醣、甲基丙烯酸氨基烷基酯共聚物E、甲基丙烯酸氨基烷基酯共聚物RS、甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、丙烯酸甲酯-甲基丙烯酸-甲基丙烯酸甲酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、聚乙烯醇缩醛二乙基氨基乙酸酯、酪蛋白、海藻酸烷基酯、明胶、聚乙二醇等水凝胶基材等。
作为用于上述巴布剂的基材,没有特别限定,例如可列举出明胶、羧甲基纤维素钠、甲基纤维素、聚丙烯酸钠、高岭土、聚乙烯醇、聚乙烯基吡咯烷酮、甘油、丙二醇、水等。
上述胶带剂优选具有含有配混成分(即,上述抗原、作为上述核受体配体剂的免疫诱导促进剂、根据需要上述第二免疫诱导促进剂等)的粘合剂层和支撑上述粘合剂层的支撑体。还可以进一步含有在使用前不使上述粘合剂层露出,在使用时能够容易地从述粘合剂层剥离的剥离衬垫。
对于形成上述粘合剂层的粘合剂,没有特别限定,例如可列举出含有丙烯酸系聚合物的丙烯酸系粘合剂;含有橡胶系弹性体的橡胶系粘合剂;有机硅橡胶、二甲基硅氧烷基质、二苯基硅氧烷基质等有机硅系粘合剂;聚乙烯基甲基醚、聚乙烯基乙基醚、聚乙烯基异丁基醚等乙烯基醚系粘合剂;乙酸乙烯酯-乙烯共聚物等乙烯基酯系粘合剂;对苯二甲酸二甲酯、间苯二甲酸二甲酯、邻苯二甲酸二甲酯等的羧酸成分与乙二醇等多元醇成分形成的聚酯系粘合剂等。其中,优选丙烯酸系粘合剂、橡胶系粘合剂、有机硅系粘合剂。由于抗原的扩散/释放性良好,因而优选聚丙烯酸钠等的亲水性基材。
上述粘合剂层中的上述粘合剂的含量,没有特别限定,作为固体成分,优选为上述粘合剂层的总重量的10~90重量%,更优选为20~80重量%。
上述丙烯酸系粘合剂含有包含(甲基)丙烯酸烷基酯作为第一单体的聚合物作为主要成分。
作为上述第一单体,可列举出:具有碳原子数1~18的直链状、支链状或环状烷基的(甲基)丙烯酸烷基酯等。其中,优选为具有碳原子数4~18的直链状、支链状或环状烷基的(甲基)丙烯酸烷基酯。进而,为了在常温下赋予粘合性,更优选使用使聚合物的玻璃化转变温度降低的单体成分,更优选为具有碳原子数4~8的直链状、支链状或环状烷基(例如,丁基、戊基、己基、环己基、庚基、辛基、2-乙基己基等,优选为丁基、2-乙基己基、环己基,特别优选为2-乙基己基)的(甲基)丙烯酸烷基酯。
作为上述第一单体,具体而言,优选为丙烯酸丁酯、丙烯酸2-乙基己酯、甲基丙烯酸2-乙基己酯、丙烯酸环己酯、甲基丙烯酸环己酯,特别优选为丙烯酸2-乙基己酯。这些第一单体可以单独使用一种或者组合2种以上使用。
上述第一单体也可以与第二单体共聚,作为这样的第二单体,可列举出:具有使用交联剂时能够成为交联点的官能团的单体。作为能够参与交联反应的官能团,可列举出羟基、羧基、乙烯基等,优选为羟基、羧基。
作为上述第二单体,具体而言,可列举出:(甲基)丙烯酸羟基乙酯、(甲基)丙烯酸羟丙基酯、N-羟基烷基(甲基)丙烯酰胺、(甲基)丙烯酸、衣康酸、马来酸、马来酸酐、中康酸、柠康酸、戊烯二酸等。其中,从获得的容易性的观点出发,优选为丙烯酸、甲基丙烯酸、丙烯酸羟基乙酯(特别是丙烯酸2-羟基乙酯),特别优选为丙烯酸。这些第二单体可以单独使用或者组合2种以上使用。
上述第一单体和第二单体也可以进一步与第三单体共聚。
作为上述第三单体,可列举出例如:乙酸乙烯酯、丙酸乙烯酯等乙烯基酯类;甲基乙烯基醚、乙基乙烯基醚等乙烯基醚类;N-乙烯基-2-吡咯烷酮、N-乙烯基己内酰胺等乙烯基酰胺类;(甲基)丙烯酸甲氧基乙酯、(甲基)丙烯酸乙氧基乙酯、(甲基)丙烯酸四氢糠基酯等(甲基)丙烯酸烷氧基酯;(甲基)丙烯酸羟丙基酯、α-羟基甲基丙烯酸酯等含羟基单体(由于作为第三单体使用,所以不是交联点);(甲基)丙烯酰胺、二甲基(甲基)丙烯酰胺、N-丁基(甲基)丙烯酰胺、N-羟甲基(甲基)丙烯酰胺等具有酰胺基的(甲基)丙烯酸衍生物;(甲基)丙烯酸氨基乙酯、(甲基)丙烯酸二甲基氨基乙酯、(甲基)丙烯酸叔丁基氨基乙酯等(甲基)丙烯酸氨基烷基酯;(甲基)丙烯酸甲氧基乙二醇酯、(甲基)丙烯酸甲氧基二乙二醇酯、(甲基)丙烯酸甲氧基聚乙二醇酯、(甲基)丙烯酸甲氧基聚丙二醇酯等(甲基)丙烯酸烷氧基亚烷基二醇酯;(甲基)丙烯腈;苯乙烯磺酸、烯丙基磺酸、(甲基)丙烯酸磺基丙酯、(甲基)丙烯酰氧基萘磺酸、丙烯酰胺甲磺酸等具有磺酸的单体;乙烯基哌啶烷酮、乙烯基嘧啶、乙烯基哌嗪、乙烯基吡咯、乙烯基咪唑、乙烯基恶唑、乙烯基吗啉等含乙烯基的单体等。其中,优选乙烯基酯类、乙烯基酰胺类;乙烯基酯类优选乙酸乙烯酯,乙烯基酰胺类优选N-乙烯基-2-吡咯烷酮。这些第三单体可以单独使用或者组合2种以上使用。
是上述(甲基)丙烯酸烷基酯(第一单体)与上述具有能够参与交联反应的官能团的乙烯基单体(第二单体)的共聚物的情况下,上述(甲基)丙烯酸烷基酯与上述具有能够参与交联反应的官能团的乙烯基单体的重量比优选为99~85:1~15,更优选为99~90:1~10。
是上述(甲基)丙烯酸烷基酯(第一单体)、上述具有能够参与交联反应的官能团的乙烯基单体(第二单体)与除此以外的其他单体(第三单体)的共聚物的情况下,上述(甲基)丙烯酸烷基酯、上述具有能够参与交联反应的官能团的乙烯基单体与除此以外的其他单体的重量比优选为40~94:1~15:5~50,更优选为50~89:1~10:10~40。
对于聚合反应,没有特别的限定,可以用现有已知的方法进行,可列举出例如:添加聚合引发剂(例如,过氧化苯甲酰、偶氮双异丁腈),在溶剂(例如,乙酸乙酯)中使上述的单体在50~70℃下反应5~48小时的方法。
上述丙烯酸系粘合剂更优选含有:丙烯酸2-乙基己酯/丙烯酸/N-乙烯基-2-吡咯烷酮的共聚物、丙烯酸2-乙基己酯/N-(2-羟基乙基)丙烯酰胺/N-乙烯基-2-吡咯烷酮的共聚物、丙烯酸2-乙基己酯/丙烯酸2-羟基乙酯/乙酸乙烯酯的共聚物、丙烯酸2-乙基己酯/丙烯酸的共聚物,特别优选含有丙烯酸2-乙基己酯/丙烯酸/N-乙烯基-2-吡咯烷酮的共聚物。
可以对上述丙烯酸系粘合剂利用紫外线照射、电子束照射等放射线照射实施物理的交联处理,也可以使用三官能性异氰酸酯等异氰酸酯系化合物、有机过氧化物、有机金属盐、金属醇盐、金属螯合化合物、多官能性化合物(例如,多官能性外部交联剂、二(甲基)丙烯酸酯等多官能性内部交联用单体)等交联剂实施化学的交联处理。
对于形成上述橡胶系粘合剂的橡胶系弹性体,没有特别的限定,可列举出例如:聚异丁烯-聚丁烯系、苯乙烯-二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯系、腈系、氯丁二烯系、乙烯基吡啶系、聚异丁烯系、丁基系、异戊二烯-异丁烯系等。其中,从对于上述配混成分的溶解性和皮肤粘接性的观点出发,优选聚异丁烯(PIB)、苯乙烯-二烯-苯乙烯嵌段共聚物(例如,苯乙烯-丁二烯-苯乙烯嵌段共聚物(SBS)、苯乙烯-异戊二烯-苯乙烯嵌段共聚物(SIS))。这些橡胶系弹性体可以单独使用一种或者组合2种以上使用。
作为上述橡胶系粘合剂,为了得到合适的粘附力和对于上述配混成分的溶解性,以同一成分或不同成分计,将平均分子量不同的橡胶系弹性体混合来使用。优选例如,平均分子量15万~550万的高分子量的聚异丁烯与平均分子量1万~15万的中分子量的聚异丁烯和/或平均分子量500~4000的低分子量聚异丁烯的混合物。相对于聚异丁烯的总体量,高分子量的聚异丁烯的配混量为10~80重量%,优选为20~70重量%。相对于聚异丁烯的总体量,中分子量的聚异丁烯的配混量为0~90重量%,优选为10~80重量%。相对于聚异丁烯的总体量,低分子量的聚异丁烯的配混量为0~80重量%,优选为10~60重量%。
本说明书中所谓的“平均分子量”是指利用Flory的粘度式计算的粘均分子量,其是由20℃下的乌氏粘度计的毛细管1的流动时间利用Schulz-Blaschke式算出斯托丁格指数(Staudinger Index)(J0),使用该J0值通过下述式求出的。
(式)
J0=ηsp/c(1+0.31ηs。)(Schulz-Blaschke式)
ηsp=t/t0-1
t:溶液的流动时间(利用Hagenbach-couette校正公式)
t0溶剂的流动时间(利用Hagenbach-couette校正公式)
c:溶液的浓度(g/cm3)
粘均分子量
在上述橡胶系粘合剂中,为了赋于适度的粘合性,可以配混例如松香系树脂、聚萜烯树脂、香豆酮-茚树脂、石油系树脂、萜烯-酚醛树脂、二甲苯树脂、脂环族饱和烃树脂等增粘剂。这些增粘剂可以单独使用1种或者组合使用2种以上。
上述增粘剂的含量以上述橡胶系粘合剂的总重量为基准优选为50重量%以下、更优选为5~40重量%。
作为上述有机硅系粘合剂,可列举出:包含有机聚硅氧烷系、聚二甲基硅氧烷系、聚二甲基二苯基硅氧烷系等的有机硅系粘合剂。其中,优选使用来自Dow CorningCorporation公司制造的BIO PSA这样的商业上能获得的有机硅系粘合剂。
上述粘合剂层也可以进一步含有皮肤渗透性增强剂。
本说明书中的“皮肤渗透性增强剂”是指能够改善经皮给药的抗原透过皮肤的效率的所有的物质。
作为上述皮肤渗透性增强剂,优选在室温(25℃)下为液态(即,具有流动性)。在混合使用2种以上的皮肤渗透性增强剂时,优选最终混合物在室温(25℃)下为液态,具有皮肤渗透促进效果。作为这样的有机液态成分,从与上述粘合剂层中的相容性的观点考虑,优选疏水性液态成分。
作为上述皮肤渗透性增强剂,可列举出:高级醇、脂肪酸酯、多元醇脂肪酸酯。
作为上述高级醇,优选碳原子数8~18的高级醇,更优选碳原子数8~14的高级醇。作为上述脂肪酸酯,优选为碳原子数8~18的脂肪酸与碳原子数1~18的一元醇的脂肪酸酯,更优选为碳原子数12~16的脂肪酸与碳原子数1~18的一元醇的脂肪酸酯。其中,优选为脂肪酸酯,特别优选为肉豆蔻酸异丙酯、棕榈酸异丙酯、癸二酸二乙酯。
上述皮肤渗透性增强剂具体可列举出油醇、辛基十二烷醇等高级醇;甘油、乙二醇、聚丙二醇等多元醇;油酸、辛酸等高级脂肪酸;肉豆蔻酸异丙酯、棕榈酸异丙酯、油酸乙酯等脂肪酸酯;癸二酸二乙酯、己二酸二异丙酯等多元酸酯;三异硬脂酸二甘油酯、单油酸失水山梨醇酯、二辛酸丙二醇酯、单月桂酸聚乙二醇酯、四油酸聚氧乙烯山梨糖醇酯等多元醇脂肪酸酯;聚氧乙烯月桂基醚等聚氧乙烯烷基醚;角鲨烷、液体石蜡等烃;橄榄油、蓖麻油等植物油;硅油;N-甲基吡咯烷酮、N-十二烷基吡咯烷酮等吡咯烷酮类;癸基甲基亚砜等亚砜。这些皮肤渗透性增强剂可以单独使用一种或者组合2种以上使用。
使用上述丙烯酸系粘合剂或上述橡胶系粘合剂的情况下,作为上述皮肤渗透性增强剂,可以使用例如,聚乙烯基吡咯烷酮、交联聚维酮、聚丙二醇、聚乙烯醇、羧基乙烯基聚合物、羟丙基纤维素或者它们的混合物。其中,优选为聚乙烯基吡咯烷酮、交联聚维酮、聚丙二醇。
对于上述粘合剂层中的上述皮肤渗透性增强剂的含量,没有特别的限定,优选为上述粘合剂层总重量的0.1~70重量%,更优选为1~65重量%,进而优选为5~60重量%。上述皮肤渗透性增强剂的含量为0.1重量%以上的情况下,能够得到高的皮肤渗透促进效果。上述皮肤渗透性增强剂的含量为70重量%以下时,能够抑制上述粘合剂层整体的粘附力、内聚力的降低且得到高的皮肤渗透促进效果。
对于上述粘合剂层的厚度,没有特别的限定,优选为10~1000μm。通过设为上述范围的厚度,从而使上述粘合剂层含有有效量的上述配混成分、使其发挥充分的粘合力、形成上述粘合剂层等变得容易。
对于上述支撑体没有特别限定,优选为实质上对上述配混成分具有不渗透性的物质,即不会发生上述粘合剂层中所含的上述抗原、作为上述核受体配体剂的免疫诱导促进剂、根据需要上述第二免疫诱导促进剂等通过支撑体而自背面流失从而含量降低的支撑体。
作为上述支撑体,例如可列举出:聚酯、聚酰胺、聚偏氯乙烯、聚乙烯、聚丙烯、聚氯乙烯、乙烯-丙烯酸乙酯共聚物、聚四氟乙烯、离聚物树脂、金属箔等单独的薄膜或它们的层叠薄膜等。其中,为了使上述支撑体与上述粘合剂层的粘接性(锚固性)提高,而优选为由上述材质形成的无孔的塑料薄膜与多孔薄膜的层叠薄膜。该情况下,上述粘合剂层优选在多孔薄膜侧形成。
作为上述多孔薄膜,只要提高与上述粘合剂层的锚固性就没有特别限定,例如可列举出纸、织布、无纺布、编织布、实施了机械穿孔处理的片等。其中,从操作性等的观点考虑,优选为纸、织布、无纺布。上述多孔薄膜的厚度从锚固性提高、胶带剂的柔软性及贴附操作性等方面考虑,优选为1~200μm。另外,织布或无纺布时,上述多孔薄膜的单位面积重量优选为5~30g/m2,更优选为6~15g/m2。
特别是作为上述支撑体,优选厚度1.5~6μm的聚酯薄膜(优选为聚对苯二甲酸乙二醇酯薄膜)与单位面积重量6~15g/m2的聚酯(优选聚对苯二甲酸乙二醇酯)制无纺布的层叠薄膜。
作为上述剥离衬垫,只要能够进行剥离处理,并确保足够轻的剥离力就没有特别限定,例如可列举出通过在与上述粘合剂层的接触面涂布有机硅树脂、氟树脂等而实施了剥离处理的聚酯、聚氯乙烯、聚偏氯乙烯、聚对苯二甲酸乙二醇酯等的薄膜、优质纸、玻璃纸等纸、优质纸或玻璃纸等与聚烯烃的层压薄膜等。
上述剥离衬垫的厚度优选为10~200μm,更优选为25~100μm。
特别是作为上述剥离衬垫,从阻隔性、价格等方面考虑,优选由聚酯(特别是聚对苯二甲酸乙二酯)树脂形成。在此情况下,从操作性方面考虑,厚度优选为25~100μm左右。
<经皮给药用免疫诱导促进用组合物>
本发明的经皮给药用免疫诱导促进用组合物在对象的各种核受体配体的经皮给药中,更有效地发挥出一起或分别给药的各种抗原诱导的免疫。
作为上述经皮给药用免疫诱导促进用组合物的制剂,可以使用与上述经皮给药用疫苗药物组合物相同的制剂。进而,对于上述经皮给药用免疫诱导促进用组合物的制剂制备,可以使用与上述经皮给药用疫苗药物组合物的制剂制备所使用的材料相同的材料。
<皮内、皮下或肌肉给药用疫苗药物组合物>
上述皮内、皮下或肌内给药用疫苗药物组合物的剂型只要是具有例如液体制剂、水溶性或疏水性的悬浮剂、霜剂等能够注射给药程度的流动性的剂型即可。这些组合物的划分、定义、性质、制法等是该技术领域公知的,可以参照例如日本药典第16版。另外,对于这些材料,没有特别的限定,可以使用现有已知的物质。
作为用于上述液体制剂的溶剂,可列举出适量的水、生理盐水、乙醇、甘油、丙二醇等。通过使上述配混成分分散或溶解在这些溶剂中,从而能够制备液体制剂。
对于上述水溶性悬浮剂所使用的基材,没有特别的限定,可列举出例如:羧基乙烯基聚合物、凝胶基质、无脂肪性软膏、聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、海藻酸钠、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、乙酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、塔拉胶、罗望子胶、车前子胶、琼脂、结冷胶、葡甘露聚糖、刺槐豆胶、瓜尔豆胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚醣、EUDRAGIT、酪蛋白、海藻酸烷基酯、明胶、聚乙二醇等水凝胶基材等。通过将这些基材溶解于溶剂中,并配混上述配混成分,从而能够制备具有流动性的悬浮剂。作为溶剂,优选为生理盐水,也可以使用甘油、丙二醇等。
作为上述疏水性悬浮剂所使用的基材,可列举出亲水性软膏、雪花膏等水/油型基材;亲水性凡士林、精制羊毛脂、阿夸弗尔、优塞林、Neocerin、含水羊毛脂、冷霜、亲水Plastibase等油/水型基材。通过将这些基材投入到油脂系溶剂或水中,利用均质器等进行高速搅拌,并配混上述配混成分,从而能够制备油脂系悬浮剂。
<皮内、皮下或肌肉给药用免疫诱导促进用组合物>
本发明的皮内、皮下或肌肉给药用免疫诱导促进用组合物在对象的各种核受体配体的皮内、皮下或肌肉给药中,更有效地发挥出一起或分别给药的各种抗原诱导的免疫。
作为上述皮内、皮下或肌肉给药用免疫诱导促进用组合物的制剂,可以使用与上述皮内、皮下或肌肉给药用疫苗药物组合物相同的制剂。进而,对于上述皮内、皮下或肌肉给药用免疫诱导促进用组合物的制剂制备,可以使用与上述皮内、皮下或肌肉给药用疫苗药物组合物的制剂制备所使用的材料相同的材料。
向对象给予本发明的疫苗药物组合物时,上述抗原的治疗上有效量根据疾病的严重程度、对象的年龄及相对的健康以及其它已知的因素而可以大范围地变化,通常,1天用量约0.1μg~1g/kg体重能够得到令人满意的结果。将上述作为核受体配体的免疫诱导促进剂与上述抗原同时或逐次给药,优选为同时给药。
另外,向对象给予本发明的免疫诱导促进用组合物时、以及向对象给予含有免疫诱导促进用组合物的疫苗药物组合物时,上述作为核受体配体的免疫诱导促进剂的治疗上有效量根据所使用的具体的核受体配体、其他免疫诱导促进剂的有无等可以在宽范围内变化,通常,1天用量约0.1μg~1g/kg体重能够得到令人满意的结果。
需要说明的是,可以将1天用量1次给药;也可以分为2次以上(例如,2次、3次、4次、5次等)多次来给药。每1次的连续给药时间优选在1分钟~7天之间适宜选择。给药间隔可以为每天1次~1年1次(例如,1天1次、2天1次、3天1次、1周1次、2周1次、1个月1次、3个月1次、6个月1次、1年1次)或者更长的给药间隔,可以根据患者的状态、疾病的重症度、治疗目的或预防目的等而适宜选择。通常,对于现实中患有重度疾病的患者的治疗目的,以更高频率和/或高用量给予本发明的疫苗药物组合物;对于不具有疾病的患者的预防目的,以更低频率和/或低用量给予本发明的疫苗药物组合物。
发明的效果
本发明的免疫诱导促进用组合物和疫苗药物组合物由于能够非侵入地体表面上的给药(例如,经皮给药或经粘膜给药)或者低侵入地皮肤表面上的给药(例如,进行胶带剥离等角质剥离处理、以及微针、电穿孔等角质穿孔处理的皮肤表面的给药等),由此能够得到优异的应变性。即,在疼痛、恐惧心理、注射痕和紧随的瘢痕化、进行重复给药的情况下经常或定期去医院成为患者的生活负担等患者的QOL观点产生的问题被降低。另外,由于给药是简便的,所以能够患者自行给药,能够避免医疗从业者的针刺感染事故的风险,不会产生注射针等需要特殊废弃的医疗废弃物。
本发明的免疫活化组合物和疫苗药物组合物有如下优点:只要为胶带剂、巴布剂等贴剂的形式,则能够切实地给予规定的给药量,能够任意地控制药物释放速度,另外,在给药时不会附着于其他部位。进而,贴剂有如下优点:由于能够容易地拆卸,所以在副作用产生的情况等通过由施用部位去除贴剂,能够由患者自己立即中止给药。
通过给予本发明的免疫诱导促进用组合物或疫苗药物组合物,与抗原的单独给药相比较,抗体产生诱导效果显著地提高。
附图说明
图1是表示将实施例1~8、比较例1~2中得到的经皮给药用霜剂经皮给药时的小鼠脾细胞中的IFN-γ产生细胞点数的评价结果的图。
图2是表示将实施例9~20、比较例3~8中得到的经皮给药用胶带剂经皮给药时的小鼠脾细胞中的IFN-γ产生细胞点数的评价结果的图。
图3是表示将实施例21~28、比较例9中得到的鼻腔给药用液体制剂鼻腔给药时的小鼠血清中OVA特异性IgG抗体效价结果的图。
图4是表示将实施例29~36、比较例10中得到的舌下给药用液体制剂舌下给药时的小鼠血清中OVA特异性IgG抗体效价结果的图。
图5是表示将实施例37~52、比较例11~12中得到的舌下给药用固体制剂舌下给药时的小鼠血清中OVA特异性IgG抗体效价结果的图。
图6是表示将实施例53~56、比较例13中得到的皮下给药用液体制剂皮下给药时的小鼠血清中OVA特异性IgG抗体效价结果的图。
图7是表示将实施例57~60、比较例14中得到的经皮给药用霜剂经皮给药时的小鼠血清中OVA特异性IgG抗体效价结果的图。
具体实施方式
以下,示出实施例,对本发明具体地进行说明,但本发明并不限定于这些实施例。
(实施例1~8、比较例1~2)
(经皮给药用霜剂的制备)
制备具有下述表1的组成的经皮给药用霜剂。具体而言,以下述表1中所示的配混量配混下述所示的抗原肽5重量%、核受体配体3重量%、根据需要的辅助肽1重量份和二甲基亚砜(DMSO)15重量%,向其中加入基材(基质霜)成为总计100重量%,进行混和,从而得到经皮给药用霜剂。使用的基质霜用表14所述的组成配混材料,混和并制备。白色凡士林、失水山梨醇单硬脂酸酯、异硬脂酸、苄醇、硬脂醇、聚山梨醇酯60、浓甘油、二甲基亚砜(DMSO)是从和光纯药工业买到的。鲸蜡醇从东京化成工业买到。
准备将PET薄膜/PET无纺布层叠品(面积0.7cm2)与固定用粘合带的中央部以PET薄膜侧作为胶带侧贴合而成的复合基材。在该复合基材的无纺布部分涂布经皮给药用霜剂4mg,将其作为免疫试验的给药样品。
(核受体配体)
维甲酸(all-trans(全反)视黄酸、和光纯药工业公司制)
异维甲酸(13-cis(顺)视黄酸、Sigma-Aldrich公司制)
阿利维甲酸(9-cis视黄酸、和光纯药工业公司制)
蓓萨罗丁(Sigma-Aldrich公司制)
(抗原肽)
OVAp(OVA肽、序列Ser Ile Ile Asn Phe Glu Lys Leu(序列号13)的8氨基酸的肽)
(辅助肽)
PADRE
<评价1>
对于实施例、比较例中得到的经皮给药用霜剂,进行以下的评价。
(细胞性免疫诱导效果的评价)
按照以下的步骤,使用经皮给药用霜剂,使用免疫评价用模型动物进行小鼠免疫试验。之后,通过ELISPOT法评价抗原特异的细胞性免疫的诱导水平。将评价结果示于图1中。
(1)免疫评价用模型动物
此处所说的“免疫评价用模型动物”是指用于评价疫苗药物组合物(此处,经皮给药用霜剂)的免疫诱导特性的模型动物,具体而言,是指用于评价经皮给药用霜剂的细胞性免疫诱导水平的模型动物。
作为免疫评价用模型动物,考虑到经皮给药用霜剂中的抗原与动物MHC类1分子的合适性,使用能够评价利用经皮给药用霜剂中的抗原的细胞性免疫诱导的动物。
即,抗原为HLA-A*24型MHC限制性类1肽的情况下,用BALB/c小鼠进行评价。抗原为HLA-A*02型MHC限制性肽的情况下,使用能够评价利用HLA-A*02型MHC限制性肽的细胞性免疫诱导的基因变异小鼠进行评价。抗原为其他HLA型的MHC限制性肽的情况下,使用能够评价利用该HLA型MHC限制性肽的细胞性免疫诱导的动物进行评价。
(2)经皮给药用霜剂的小鼠免疫试验
将下述表1中所示的小鼠的背部剃毛,设置用于使由剃毛带来的皮肤损伤恢复的饲养期间,之后,对小鼠的背部皮肤给予经皮给药用霜剂4mg 24小时,去除,进行6天的饲养。自给药起经过6天之后摘除脾脏,制备脾细胞悬浊液。向固定化了抗小鼠IFN-γ抗体的ELISPOT平板的孔中,与培养液一起加入脾细胞(1×106个细胞/孔)和抗原肽(100μM),在37℃、5%CO2的培养条件下进行20小时共培养,用ELISPOT法评价IFN-γ产生细胞点数。将IFN-γ产生细胞点数作为“免疫结果”示于下述表1中。
[表1]
(实施例9~20、比较例3~8)
(经皮给药用胶带剂的制备)
制备具有下述表2组成的经皮给药用胶带剂。具体而言,以下述表2中所示的配混量配混下述所示的抗原肽、核受体配体和辅助肽,在其中将下述表2中所示的粘性基材和有机溶剂(乙酸乙酯)以有机溶剂干燥后的各成分与粘性基材的总计成为100重量%的方式进行配混、混和,从而制备粘合剂溶液。以干燥后的厚度成为约80μm的方式将得到的粘合剂溶液涂敷于剥离衬垫,通过干燥去除有机溶剂,从而形成粘合剂层。作为剥离衬垫,使用实施了有机硅剥离处理的聚对苯二甲酸乙二酯(PET)制衬垫(厚度75μm)。使得到的粘合剂层与支撑体贴合,从而得到经皮给药用胶带剂。作为支撑体,使用聚对苯二甲酸乙二酯(PET)薄膜(厚度25μm)。
将该经皮给药用胶带剂以成为面积0.7cm2的方式切出,将其作为免疫实验的给药样品。给药时,将剥离衬垫剥离进行给药。
(核受体配体)
维甲酸(all-trans视黄酸、和光纯药工业公司制)
(抗原肽)
HER2/neu_E75(HER2/neu_E75肽、癌抗原肽)
IPEP87(IPEP87肽、来自感染性病原体的抗原)
MAGE-A3_A02(MAGE3_A02肽、癌抗原肽)
(辅助肽)
PADRE
(粘性基材)
丙烯酸(在非活性气体气氛下,使丙烯酸2-乙基己酯75份、N-乙烯基-2-吡咯烷酮22份、丙烯酸3份和偶氮双异丁腈0.2份在乙酸乙酯中60℃下进行溶液聚合而得到的丙烯酸系粘合剂溶液)
PIB(将聚异丁烯(OppanolB200、BASF公司制)24份、聚异丁烯(OppanolB12、BASF公司制)36份和脂环族系石油树脂(AlconP-100、荒川化学公司制)40份溶解于甲苯中而得到的PIB粘合剂溶液)
<评价2>
对于实施例、比较例中得到的经皮给药用胶带剂,进行以下的评价。
(细胞性免疫诱导效果的评价)
通过与经皮给药用霜剂的评价同样的操作,对抗原特异的细胞性免疫的诱导水平进行评价。将评价结果示于图2中。
[表2]
(实施例21~36、比较例9~10)
(经粘膜给药用液体制剂的制备)
制备具有下述表3和4组成的经粘膜给药(鼻腔给药或舌下给药)用液体制剂。具体而言,以下述表3和4中所示的配混量将抗原(卵清蛋白(OVA))、作为核受体配体的免疫诱导促进剂配混,向其中加入生理盐水,鼻腔给药为10μL或者舌下给药为30μL,进行混和,从而得到经粘膜给药(鼻腔给药或舌下给药)用液体制剂。
(核受体配体)
维甲酸(all-trans视黄酸、和光纯药工业公司制)
异维甲酸(13-cis视黄酸、Sigma-Aldrich公司制)
阿利维甲酸(9-cis视黄酸、和光纯药工业公司制)
左旋甲状腺素钠水合物(Sigma-Aldrich公司制)
碘塞罗宁(Sigma-Aldrich公司制)
氯米芬柠檬酸盐(Sigma-Aldrich公司制)
雷洛昔芬盐酸盐(LKT Laboratories公司制)
他莫昔芬柠檬酸盐(和光纯药工业公司制)
(实施例37~52、比较例11~12)
(舌下给药用固体制剂的制备)
制备具有下述表5组成的舌下给药用固体制剂(冷冻干燥制剂或薄膜剂)。具体而言,以下述表5中所示的配混量配混抗原(卵清蛋白(OVA))、作为核受体配体的免疫诱导促进剂、作为基材的羟丙基纤维素(HPC-SSL、日本曹达公司制),向其中加入生理盐水,进行混和,从而得到制剂溶液。之后,分注制剂溶液25mg,进行冷冻干燥而得到冷冻干燥制剂,或者进行减压干燥而得到薄膜剂。对于作为核受体配体的免疫诱导促进剂,可以使用与经粘膜给药用液体制剂的制备中所使用的免疫诱导促进剂同样的物质。
<评价3>
对于实施例、比较例中得到的经粘膜给药用液体制剂或舌下给药用固体制剂,进行以下的评价。
(体液免疫诱导效果的评价)
按照以下的步骤,使用经粘膜给药用液体制剂或舌下给药用固体制剂,使用免疫评价用模型动物进行小鼠免疫试验。之后,通过测定小鼠血清中的抗原(OVA)特异性IgG抗体,评价全身性免疫应答。将评价结果示于图3~5中。
(1)经粘膜给药用液体制剂或舌下给药用固体制剂的小鼠免疫试验
对于预先准备的小鼠(BALB/c小鼠、雌性7周龄)进行麻醉处理之后,对于各小鼠,鼻腔给药(实施例21~28、比较例9)10μL、舌下给药(实施例29~36、比较例10)30μL的经粘膜给药用液体制剂,另外,给予舌下给药用固体制剂(实施例37~52、比较例11~12)。在该给药1周之后,再次对小鼠实施麻醉,分别进行同样的给药。由第2次给药起进而1周之后,采集小鼠血清。
(2)ELISA法
(小鼠血清中的抗原特异性IgG抗体效价测定方法(ELISA法))
向ELISA用96孔平板中添加用碳酸缓冲液稀释的含有OVA的溶液(100μg/mL)各100μL,放置一晩。
将事先预备的清洗液(含Tween20的PBS)清洗3次孔,将封闭剂(Block Ace、大日本住友制药公司制)用纯化水稀释成4g/100mL的封闭溶液对各孔各添加200μL,在室温下放置2小时。之后,用清洗液清洗3次孔。
对采集的小鼠血清在4℃、3000g下进行10分钟离心分离,并回收上清。使用将封闭剂用磷酸盐缓冲液(NACALAI TESQUE,INC.制)稀释至0.4g/100mL而成的溶液,将上清各2倍梯度稀释,将该溶液分别向孔中各添加50μL,在室温下放置2小时。
之后,用清洗液清洗3次孔。用将封闭剂用磷酸盐缓冲液(NACALAI TESQUE,INC.制)稀释至0.4g/100mL的溶液,将HRP标记的抗小鼠IgG抗体(Goat-anti mouse IgG FcHRP、BETHYL)稀释至10000倍,向孔中各添加100μL该溶液,在室温下放置1小时。
之后,用清洗液对孔进行3次清洗,向孔中添加TMB溶液(ELISA POD TMB试剂盒、NACALAI TESQUE,INC.制)各100μL,在暗处放置30分钟。
之后,向孔中添加各100μL、1M硫酸用液,对于该96孔平板,用酶标仪(SpectraMaxM2e、Molecular Devices公司制)测定450nm的吸光度。基于梯度稀释时的吸光度,用Log2求出小鼠血清中的IgG抗体效价。
[表3]
[表4]
[表5]
(实施例53~56、比较例13)
(皮下给药用液体制剂的制备)
制备具有下述表6组成的皮下给药用制剂。具体而言,以下述表6中所示的配混量配混抗原(卵清蛋白(OVA))、作为核受体配体的免疫诱导促进剂,向其中加入生理盐水制成为200μL、进行混和,得到皮下给药用液体制剂。
<评价4>
对于实施例、比较例中得到的皮下给药用制剂,进行以下的评价。
(体液免疫诱导效果的评价)
按照以下的步骤,使用皮下给药用制剂、使用免疫评价用模型动物进行小鼠免疫试验。之后,通过测定小鼠血清中的抗原(OVA)特异性IgG抗体,评价全身性免疫应答。将评价结果示于图6中。
(1)皮下给药用制剂的小鼠免疫试验
对于预先准备的小鼠(BALB/c小鼠、雌性7周龄)进行了麻醉处理之后,对于各小鼠,对于小鼠背部皮下给药200μL。在该给药1周之后,再次对小鼠实施麻醉,分别进行同样的给药。由第2次给药起进而1周之后,采集小鼠血清。
(2)ELISA法
通过与<评价3>相同的操作,通过ELISA法测定小鼠血清中的抗原(OVA)特异性IgG抗体。
[表6]
(实施例57~60、比较例14)
(经皮给药用霜剂的制备)
制备具有下述表7组成的经皮给药用霜剂。具体而言,以下述表7中所示的配混量,配混抗原(卵清蛋白(OVA))、核受体配体,向其中加入基材(基质霜)成为总100重量份,进行混和,得到经皮给药用霜剂。使用的基质霜用表14所述的组成配混材料,混和并制备。
对于作为核受体配体的免疫诱导促进剂,使用与鼻腔或舌下给药用液体制剂的制备中所使用的免疫诱导促进剂同样的物质。白色凡士林、失水山梨醇单硬脂酸酯、异硬脂酸、苄醇、硬脂醇、聚山梨醇酯60、浓甘油从和光纯药工业买到。鲸蜡醇从东京化成工业买到。
准备将PET薄膜/PET无纺布层叠品(面积0.7cm2)与固定用粘合带的中央部以PET薄膜侧作为胶带侧贴合而成的复合基材。该复合基材的无纺布部分涂布经皮给药用霜剂4mg,将其作为小鼠免疫试验的给药样品。
<评价5>
对于实施例、比较例中得到的经皮给药用霜剂,进行以下的评价。
(体液免疫诱导效果的评价)
按照以下的步骤,使用经皮给药用霜剂,使用免疫评价用模型动物进行小鼠免疫试验。之后,通过测定小鼠血清中的抗原(OVA)特异性IgG抗体,评价全身性免疫应答。将评价结果示于图7中。
(1)经皮给药用霜剂的小鼠免疫试验
预先将小鼠(C57BL6NCr小鼠、雌性7周龄)右背部剃毛,设置用于使由剃毛导致的皮肤损伤恢复的饲养期间,对小鼠的右背部皮肤给予经皮给药用霜剂4mg。同时将左背部剃毛。24小时后,去除右背部的经皮给药用霜剂。由该给药1周之后,对小鼠的左背部皮肤同样地给予经皮给药用霜剂,24小时后去除。由第2次给药起进而1周之后,采集小鼠血清。
(2)ELISA法
通过与<评价3>相同的操作,通过ELISA法测定小鼠血清中的抗原(OVA)特异性IgG抗体。
[表7]
(实施例61~180、比较例15~54)
制备具有下述表8~12组成的经粘膜给药(鼻腔给药或舌下给药)用液体制剂。具体而言,以下述表8~12中所示的配混量配混抗原和核受体配体,鼻腔给药时向其中加入生理盐水设为10μL;舌下给药时向其中加入生理盐水设为30μL,进行混和,从而得到经粘膜给药(鼻腔给药或舌下给药)用液体制剂。
作为抗原、作为流感疫苗抗原,使用含有流感疫苗抗原的溶液H1N1(A/California/07/2009、阪大微生物病研究会制)、H3N2(A/Victoria361/2011、阪大微生物病研究会)、B型(B/Wisconsin/1/2010、阪大微生物病研究会)、B型(B/Brisbane/60/2008、阪大微生物病研究会)。使用了含有肺炎球菌荚膜多糖的溶液(Pneumovax NP、MSD公司制造)、含有HPV16重组蛋白的溶液(HPV16、PROSPEC公司制造)、含有减毒活轮状病毒的溶液(RotaTeq口服溶液、MSD公司制造)、含有灭活脊髓灰质炎病毒的溶液(Imovax Polio皮下注射剂、Sanofi公司制造)、含有灭活甲型肝炎病毒的溶液(Aimmugen、化学及血清疗法研究所公司制造)、含有灭活乙型脑炎病毒的溶液(Encevac皮下注射用、化学及血清疗法研究所公司制造)、含有减毒活腮腺炎病毒的溶液(流行性感冒活疫苗、北里第一三共疫苗株式会社制造)、含有减毒活麻疹病毒的溶液(麻疹活疫苗、北里第一三共疫苗株式会社制造)、含有减毒活风疹病毒的溶液(干燥减毒活风疹疫苗、北里第一三共疫苗株式会社制造)、含有破伤风类毒素结合流感菌b型多糖的溶液(ActHIB、Sanofi公司制造)、含有重组HBs抗原蛋白的溶液(Bimmugen、化学及血清疗法研究所公司制造)、含有减毒活黄热病毒的溶液(黄热疫苗、Sanofi公司制造)、含有破伤风类毒素的溶液(破伤风类毒素、Denka Seiken Co.,Ltd.制造)、含有减毒活水痘病毒的溶液(干燥减毒活水痘疫苗、阪大微生物病研究会公司制造)、含有活BCG(卡介苗)的溶液(干燥BCG疫苗、日本BCG制造株式会社制造)、含有灭活狂犬病病毒的溶液(组织培养灭活狂犬病疫苗、化学及血清疗法研究所公司制造)。
对于作为核受体配体的免疫诱导促进剂,使用维甲酸(all-trans视黄酸、和光纯药工业公司制)、碘塞罗宁(Sigma-Aldrich公司制)、他莫昔芬柠檬酸盐(和光纯药工业公司制)。
<评价6>
对于实施例、比较例中得到的经粘膜给药用液体制剂,进行以下的评价。
(体液免疫诱导效果的评价)
按照以下的步骤,使用经粘膜给药用液体制剂、使用免疫评价用模型动物进行小鼠免疫试验。之后,通过测定小鼠血清中的抗原特异性IgG抗体,评价全身性免疫应答。
(1)经粘膜给药用液体制剂的小鼠免疫试验
通过进行与经粘膜给药用液体制剂或舌下给药用固体制剂的评价即<评价3>同样的操作,采集小鼠血清。
(2)ELISA法
通过进行与经粘膜给药用液体制剂或舌下给药用固体制剂的评价即<评价3>同样的操作,通过ELISA法测定小鼠血清中的抗原特异性IgG抗体。
通过上述体液免疫诱导效果的评价,经粘膜给药(鼻腔给药或舌下给药)包含作为核受体配体的免疫诱导促进剂的经粘膜给药用液体制剂(实施例21~36)的情况下,与不包含作为核受体配体的免疫诱导促进剂的经粘膜给药用液体制剂(比较例9、10)相比较,能够得到高的抗原特异性IgG抗体效价。
即,使用如下述表8~12所示的抗原的情况下,也通过使用作为核受体配体的免疫诱导促进剂,从而能够得到高的抗原特异性IgG抗体效价。
[表8]
[表9]
[表10]
[表11]
[表12]
(实施例181~184、比较例55)
按照与表7的经皮给药用霜剂相同的要领,制备具有表13组成的经皮给药用霜剂。将小鼠(C57BL6NCr小鼠、雌性7周龄)的右背部剃毛,对用日东电工制OPP胶带(EZ DunplonNo.3301EZ)实施了5次角质剥离处理的皮肤给药霜剂(低侵入给药)。同时将左背部剃毛。24小时后,去除右背部的经皮给药用霜剂。在该给药1周后,对于小鼠的左背部皮肤同样地进行角质剥离处理,给药经皮给药用霜剂,24小时后去除。由第2次给药进而1周之后,采集小鼠血清,通过ELISA法测定小鼠血清中的抗原(OVA)特异性IgG抗体。利用该低侵入给药的免疫方法,能够对于给药抗原诱导特异的体液免疫。
[表13]
[表14]
产业上的可利用性
本发明的免疫诱导促进用组合物和疫苗药物组合物能够普遍地用于对各种抗原的免疫诱导,不仅用于皮下给药也优选用于经皮给药或经粘膜给药。
序列表
<110> 日东电工株式会社(NITTO DENKO CORPORATION)
<120> 包含核受体配体的免疫诱导促进用组合物以及疫苗药物组合物
<130> F6316WO
<150> JP2014-159000
<151> 2014-08-04
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Claims (8)
1.一种免疫诱导促进用组合物,其特征在于,包含核受体配体。
2.根据权利要求1所述的免疫诱导促进用组合物,其中,核受体配体是选自由类视黄醇受体激动剂、类视黄醇X受体激动剂、甲状腺激素受体激动剂和雌激素受体调节剂组成的组中的至少一种。
3.根据权利要求1所述的免疫诱导促进用组合物,其中,核受体配体为选自由类视黄醇受体激动剂、甲状腺激素受体激动剂和雌激素受体调节剂组成的组中的至少一种,用于体液免疫诱导。
4.根据权利要求1所述的免疫诱导促进用组合物,其中,核受体配体为类视黄醇受体激动剂和/或类视黄醇X受体激动剂,用于细胞性免疫诱导。
5.根据权利要求1、2、3或4所述的免疫诱导促进用组合物,其进而包含辅助肽。
6.一种疫苗药物组合物,其特征在于,包含用于免疫诱导的抗原、和权利要求1、2、3、4或5所述的免疫诱导促进用组合物。
7.根据权利要求6所述的疫苗药物组合物,其对体表面上给药。
8.根据权利要求6所述的疫苗药物组合物,其通过皮内注射、皮下注射或肌肉注射给药。
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